The dynamics of blocking action of Na channels by local anesthetics and antiarrhythmic drugs was studied in voltage-clamped squid axons. With intact Na inactivation, local anesthetics including procaine, lidocaine, Qx-314, Qx-572 and 9-aminoacridine and antiarrhythmic drugs including quinidine, procainamide, lidocaine, propranolol, and diphenylhydantoin, exhibit frequency-dependent block and voltage-dependent block. The frequency-dependent block of Na channels manifested itself as a cumulative decrease in Na currents and the voltage-dependent block was reflected as an enhancement in blocking potency when the axon was conditioned to a more depolarized potential. The similarity of block caused local anesthetics and by antiarrhythmic drugs suggests that there is a common denominator for local anesthetic block of Na channels in nerve membrane and for the block of similar channels in cardiac membranes caused by antiarrhythmic drugs. Upon removal of Na inactivation these characteristics of block were affected to variable degrees depending on the drug applied. For example, the frequency dependence was lost or became dramatically diminished with procaine, Qx-314, and 9-aminoacridine but retained with Qx-572. The voltage dependence disappeared or was altered with procaine, Qx-314, and Qx-572, but remained intact with 9-AA. These results suggest the notion that Na inactivation modulates the blocking action on the Na channel by local anesthetics.